Abnormalities in hippocampal-prefrontal function are associated with impairments in fear regulation in humans, rats, and mice. Despite the known associations between function in these brain regions and fear expression, there is a fundamental gap in our understanding of how dysfunction in this circuit leads to expression deficits. Continued existence of this gap represents an important problem because a thorough understanding of how anatomically-defined neural circuits contribute to fear will likely be critical for the development of treatments for disorders featuring dysregulation of fear expression. The long-term goal is to better understand how altered molecular and cellular function in anatomically-connected populations of neurons contributes to fear dysregulation in neuropsychiatric disorders, and to use this information to develop novel treatment strategies for these disorders by selectively targeting clinically-relevant molecules within these populations. The overall objective of this proposal, and the first step toward our long-term goal, is to establish a causal link between one such molecule, brain-derived neurotrophic factor (BDNF), fear expression, and an anatomically-connected neural circuit, comprised of ventral hippocampal (vHC) neurons with direct projections to the prelimbic cortex (PrL), or vHC-PrL projectors. Our central hypothesis is that BDNF signaling impacts the ability of vHC-PrL projectors to bi-directionally regulate fear expression. The rationale for the proposed research is that, once causal links between hippocampal-prefrontal function, Bdnf, and fear expression are established, the selective manipulation of Bdnf in the hippocampal-prefrontal pathway will lead to therapeutic approaches to fear dysregulation that target only the affected neural circuitry. The central hypothesis of the proposal will be tested by pursuing three Specific Aims: 1) Examine how altered activity-dependent BDNF signaling impacts the structure and function of vHC-PrL projectors, 2) determine whether over-expression of BDNF in vHC-PrL projectors reverses fear-related behavioral and molecular phenotypes in the PrL of mice with impaired hippocampal-prefrontal function, and 3) investigate how aberrant BDNF-dependent plasticity impacts population dynamics in the prelimbic cortex during fear expression. The approach is innovative because it investigates the role of a selective neural circuit in fear expression with heretofore impossible anatomical specificity; furthermore, it proposes the use of cutting edge techniques to causally link Bdnf with function of this circuit during fear expression and fear-related population dynamics, which has never before been done. The proposed research is significant because the results are expected to vertically advance our understanding of the neural circuitry underlying fear expression, as well as provide potential avenues for anatomically-localized therapeutic targeting in disorders featuring fear dysregulation. It is likely that such selective targeting of neural circuitry in these disorders will be efficacious in reducing both the symptoms of these disorders and the side effects associated with current pharmacological treatments, which act non-specifically in the brain.